Focal Segmental Glomerulosclerosis (FSGS) Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: FSGS is a primary cause of idiopathic nephrotic syndrome in adults and a significant cause of End-Stage Renal Failure (ESRF) in our population. Identifying it early is crucial to try and preserve renal function.
High-Yield Definition: FSGS is a histopathological diagnosis, not a single disease. It describes a pattern of kidney injury characterized by sclerosis (scarring) that is 'focal' (affecting some, but not all, glomeruli) and 'segmental' (affecting only a part of the individual glomerulus). It is a major cause of steroid-resistant nephrotic syndrome.
Clinical One-Liner: It's a key cause of nephrotic syndrome in adults, where parts of the kidney filters scar over, leading to heavy protein leak and, if we don't intervene, progression to dialysis.
II. Etiology & Risk Factors
Etiology: We classify it by cause. This is critical as it dictates management.
Primary (Idiopathic): We assume a circulating permeability factor (like suPAR, though this is mainly research) causing diffuse podocyte (foot process) injury. This is a diagnosis of exclusion.
Secondary: This is a reactive scarring process.
Virus-associated: HIV (HIVAN - often the collapsing variant), Parvovirus B19.
Drug-induced: Heroin, long-term pamidronate, anabolic steroids.
Adaptive: Due to reduced renal mass or hyperfiltration. Think long-standing obesity, reflux nephropathy, previous kidney donation, or any other cause of Chronic Kidney Disease (CKD).
Genetic: Due to mutations in podocyte-related genes (e.g., APOL1, NPHS1, NPHS2).
Risk Factors:
Obesity
HIV infection
Heroin use
Family history of kidney disease
III. Quick Pathophysiology
The central event is podocyte injury. Podocytes are the cells lining the outside of the glomerular capillaries, and their "foot processes" create the final filtration barrier.
Injury: In primary FSGS, a circulating factor attacks the podocytes. In secondary FSGS, hyperfiltration or viruses cause damage.
Effacement: The foot processes flatten and fuse (effacement).
Proteinuria: The filtration barrier breaks, allowing massive amounts of protein (especially albumin) to leak into the urine. This causes the "nephrotic syndrome."
Sclerosis: Damaged podocytes detach, exposing the glomerular basement membrane. This triggers a scarring (sclerosis) response, which is irreversible and destroys that part of the nephron. As more nephrons scar, GFR falls, leading to ESRF.
IV. Classification
We use two systems:
Etiological (as above): Primary, Secondary, Genetic. This is the most important for management.
Histological (Columbia Classification): This is from the biopsy report and has prognostic value.
Tip Variant: Lesion at the tubular pole. Best prognosis, often responds well to steroids.
Cellular Variant: Segmental endocapillary hypercellularity.
Perihilar Variant: Scarring near the vascular pole. Often seen in secondary/adaptive FSGS.
Collapsing Variant: The worst. Characterised by retraction and collapse of the entire glomerular tuft. Rapidly progressive to ESRF. Strongly associated with HIV.
Not Otherwise Specified (NOS): The most common type.
V. Clinical Assessment
🚩 Red Flags & Immediate Actions
Anasarca with respiratory distress: Signifies pulmonary oedema or large pleural effusions. Action: Sit patient up, give high-flow O2, stat IV Furosemide. Get a CXR.
Sudden calf pain/swelling or pleuritic chest pain: High suspicion for DVT/PE (hypercoagulable state from nephrotic syndrome). Action: Escalate immediately, request D-dimer and urgent CT Pulmonary Angiogram (CTPA) or Doppler USS. Start anticoagulation.
Rapidly rising creatinine (AKI): Suggests aggressive disease (e.g., collapsing variant) or a complication like renal vein thrombosis. Action: Stat renal ultrasound with Doppler, review fluid status, hold nephrotoxins.
History
Key Diagnostic Clues:
"Frothy urine" (buih-buih) – this is the classic sign of heavy proteinuria.
Progressive peripheral oedema (pitting). Starts periorbital (worse in AM), becomes pedal (worse in PM), then ascends to anasarca (scrotal/labial oedema, ascites).
Unexplained weight gain (this is all fluid).
Symptom Breakdown:
Common (>50%): Oedema, frothy urine, fatigue.
Less Common (10-50%): Dyspnoea (pleural effusion), abdominal distension (ascites), uncontrolled hypertension (especially in secondary FSGS).
Rare (<10%): Symptoms of thromboembolism (DVT/PE).
Pertinent Negatives:
No systemic symptoms: (e.g., fever, malar rash, joint pain) – points away from Lupus Nephritis.
No recent sore throat/skin infection: – points away from post-streptococcal glomerulonephritis.
No haematuria (usually): FSGS is typically "bland" sediment. Presence of haematuria might suggest an active "nephritic" component.
Physical Examination (OSCE Approach)
General Inspection: Patient may be comfortable at rest, or tachypnoeic (pulmonary oedema). Look for signs of anasarca (puffy face, swollen limbs), pallor (anaemia of CKD).
Vitals: Hypertension is common and a key management target. Tachycardia and tachypnoea if fluid overloaded.
Disease-Specific Examination (Fluid Status):
JVP: Will be elevated if hypervolaemic.
Lungs: Check for stony dull percussion and reduced air entry at bases (pleural effusion) or fine crepitations (pulmonary oedema).
Abdomen: Check for ascites (shifting dullness, fluid thrill).
Limbs: Check for pitting oedema (press over shin for 5 seconds). Grade it (+ to +++). Check for DVT signs (calf tenderness, warmth, Homan's sign is unreliable).
Examination for Differentials:
Look for malar rash, discoid rash (SLE).
Look for signs of chronic liver disease (stigmata) or heart failure (other causes of oedema).
Look for cachexia or lymphadenopathy (HIV).
Differentiating Disease Stage:
Early: Non-nephrotic proteinuria (e.g., 1-2g/day), no oedema, normal GFR.
Moderate: Full nephrotic syndrome (proteinuria >3.5g/day, albumin <30), peripheral oedema, preserved GFR.
Late / Severe: Nephrotic syndrome with complications (anasarca, thrombosis), uncontrolled hypertension, and/or declining GFR (CKD).
Clinical Pearl: Your diuretic "challenge" is also diagnostic. A patient with nephrotic oedema is often intravascularly deplete despite being water-logged. They can be very sensitive to diuretics and become hypotensive, or very resistant. Go carefully.
VI. Diagnostic Workflow
Differential Diagnosis
Minimal Change Disease (MCD):
Points For: Presents as full-blown nephrotic syndrome.
Points Against: Much more common in children. In adults, FSGS and Membranous are more common.
How to Differentiate: Renal biopsy. LM will be normal in MCD. EM shows diffuse foot process effacement (which FSGS also has, but FSGS has sclerosis on LM).
Membranous Nephropathy (MN):
Points For: Common cause of nephrotic syndrome in adults.
Points Against: Tends to be less aggressive, more associated with thrombosis.
How to Differentiate: Renal biopsy. IF shows "lumpy-bumpy" IgG/C3 deposits. EM shows "spikes and domes." Can also check anti-PLA2R antibody in serum.
Lupus Nephritis (Class IV or V):
Points For: Can present with nephrotic-range proteinuria.
Points Against: Usually has other systemic features of SLE.
How to Differentiate: Serology (ANA, anti-dsDNA, low C3/C4) and biopsy ("full-house" immunofluorescence).
Investigations Plan
Bedside / Initial (First 15 Mins):
UFEME (Urine FEME): This is your most important first test. Look for Protein 3+ or 4+. May see oval fat bodies (Maltese crosses under polarised light).
ECG: Check for signs of hyperkalaemia or ischaemia if BP is high.
First-Line Labs & Imaging:
Renal Profile (RP): To check Creatinine (for GFR) and Urea.
Liver Function Test (LFT): Crucial. Look for low serum albumin (e.g., <30 g/L).
Fasting Lipid Profile: Expect high cholesterol/triglycerides (hyperlipidaemia is part of nephrotic syndrome).
Urine Protein:Creatinine Ratio (UPCR) or 24-hour Urine Protein: To quantify the proteinuria.
Full Blood Count (FBC): May show high haematocrit (haemoconcentration).
Secondary Cause Screen:
Viral markers: HIV, Hepatitis B, Hepatitis C.
Autoimmune screen: ANA, C3, C4, anti-dsDNA.
Renal Ultrasound: To assess kidney size, echogenicity, and rule out obstruction.
Confirmatory / Gold Standard:
Percutaneous Renal Biopsy: This is the only way to diagnose FSGS definitively. The sample must be sent for:
Light Microscopy (LM): To see the focal and segmental sclerosis.
Immunofluorescence (IF): To rule out immune-complex disease (e.g., Lupus, IgA). It's typically negative in Primary FSGS.
Electron Microscopy (EM): To see the diffuse podocyte foot process effacement.
VII. Staging & Severity Assessment
Severity is based on three things:
Clinical Presentation: Non-nephrotic proteinuria (<3.5g/day) vs. Full Nephrotic Syndrome (>3.5g/day, low albumin, oedema).
Histological Variant: Collapsing variant is the most severe. Tip variant is the mildest.
Renal Function: Normal GFR vs. CKD stage.
VIII. Management Plan
A. Principle of Management
Reduce Proteinuria: This is the primary goal to slow GFR decline.
Manage Complications: Treat oedema, hypertension, hyperlipidaemia, and hypercoagulability.
Treat the Cause: Immunosuppression for Primary FSGS, specific treatment for Secondary FSGS.
B. Immediate Stabilisation (The ABCDE Plan)
This is typically for complications, not the FSGS itself.
A/B: If pulmonary oedema: High-flow O2, sit up.
C: If severe hypertension: IV Labetalol or hydralazine. If fluid overloaded: IV Furosemide (may need high doses, e.g., 80-120mg stat).
If DVT/PE suspected: Start therapeutic-dose Clexane (enoxaparin) immediately.
C. Definitive Treatment (The Ward Round Plan)
1. Supportive Management (FOR ALL PATIENTS):
RAAS Blockade: Mandatory. Start an ACE inhibitor (e.g., Perindopril 2-4mg OD) or ARB (e.g., Losartan 25-50mg OD). This is not just for BP; it directly reduces proteinuria. Titrate to max tolerated dose.
Diuretics: For oedema. Oral Furosemide (40-80mg OD/BD). May need to add a thiazide (e.g., Metolazone) or Spironolactone if resistant.
Statins: For hyperlipidaemia (e.g., Simvastatin 20-40mg ON).
Diet: Low salt (<2g/day) and fluid restriction (~1.5L/day) if oedematous.
Anticoagulation: We use this if serum albumin is very low (e.g., <20-25 g/L) due to high risk of thrombosis. Prophylactic or therapeutic, depending on patient.
2. Disease-Specific Management:
If Primary FSGS: This is an autoimmune disease. We give immunosuppression.
First-Line: High-dose oral corticosteroids. Prednisolone 1mg/kg/day (max 60-80mg) for at least 4-16 weeks to assess for response, then a very slow taper over 6 months.
Second-Line (Steroid-Resistant/Intolerant): Calcineurin Inhibitors (CNIs) like Cyclosporine or Tacrolimus. We monitor trough levels. Other options include Mycophenolate Mofetil (MMF).
If Secondary FSGS: DO NOT IMMUNOSUPPRESS. You will harm the patient. The management is to treat the underlying cause.
HIVAN: Start highly active antiretroviral therapy (HAART).
Obesity-related: Weight loss, bariatric surgery.
Drug-induced: Stop the offending drug.
Adaptive: Max out RAAS blockade.
D. Long-Term & Discharge Plan
Follow-up: Regular Nephrology clinic follow-up is lifelong.
Monitoring: Patient must monitor weight, BP, and urine dipstick (for protein) at home.
Medication: Emphasise compliance with RAAS blockade and immunosuppressants.
Counselling: Explain steroid side effects (Cushingoid, diabetes, infections, osteoporosis - give calcium/Vit D). Counsel on high risk of cardiovascular disease.
IX. Complications
Immediate/Short-Term:
Thromboembolism (DVT/PE, Renal Vein Thrombosis): Due to loss of anticoagulant proteins (Antithrombin III) in urine. Action: High suspicion, prophylactic/therapeutic anticoagulation.
Severe Infections: Especially Spontaneous Bacterial Peritonitis (SBP) and cellulitis. Due to loss of immunoglobulins in urine. Action: Low threshold to start antibiotics, ensure vaccinations (Pneumococcal).
Acute Kidney Injury (AKI): From intravascular volume depletion, diuretics, or the disease itself.
Long-Term:
End-Stage Renal Failure (ESRF): This is the main fear. Up to 50% of primary FSGS patients may reach ESRF in 10 years.
Cardiovascular Disease: Hyperlipidaemia, HTN, and CKD create a very high ASCVD risk.
Complications of Treatment: Long-term steroid and CNI toxicity.
X. Prognosis
Highly variable.
Good Prognostic Factors: Tip variant, presentation with non-nephrotic proteinuria, good response to steroids (achieving remission).
Poor Prognostic Factors: Collapsing variant (often 50% ESRF at 2 years), steroid-resistance, high creatinine at presentation, severe persistent proteinuria.
XI. How to Present to Your Senior
Use the SBAR format.
"Mdm/Sir, good morning. I'm calling about Mr. Lim, a 38-year-old gentleman in Bed 5, admitted for anasarca.
S (Situation): He was admitted via GOPD for 3 weeks of progressive leg swelling and frothy urine.
B (Background): He is otherwise well with no known medical illness.
A (Assessment): His vitals are stable, BP 145/90. Examination shows anasarca with pitting oedema up to the mid-shin and ascites.
UFEME shows Protein 4+.
Lab results show: Serum Albumin 19, Creatinine 110, UPCR 800 g/mol.
My clinical impression is new-onset Nephrotic Syndrome.
R (Recommendation): I have sent off the full nephrotic screen including viral markers and autoimmune screen. I am managing him with salt restriction and have started oral Furosemide 40mg OD. I would like to request your review for counselling and consent for a renal biopsy to confirm the diagnosis, likely FSGS or MCD."
XII. Summary & Further Reading
Top 3 Takeaways
FSGS is a histologic diagnosis for a major cause of adult nephrotic syndrome.
You MUST differentiate Primary (needs immunosuppression) from Secondary (treat the cause) FSGS. A biopsy is mandatory.
All patients need supportive care: RAAS blockade (ACEi/ARB) for proteinuria, diuretics for oedema, statins for lipids, and often anticoagulation.
Key Resources
UpToDate: "Treatment of minimal change disease and focal segmental glomerulosclerosis in adults" and "Etiology, clinical features, and diagnosis of focal segmental glomerulosclerosis"
KDIGO Guidelines: These are the international guidelines we follow. Look up the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.
Amboss: "Focal segmental glomerulosclerosis"
